Apolipoprotein E-low density lipoprotein receptor interaction affects spatial memory retention and brain ApoE levels in an isoform-dependent manner

Lance A. Johnson, Reid H.J. Olsen, Louise S. Merkens, Andrea DeBarber, Robert D. Steiner, Patrick M. Sullivan, Nobuyo Maeda, Jacob Raber

Research output: Contribution to journalArticlepeer-review

58 Scopus citations


Human apolipoprotein E (apoE) exists in three isoforms: apoE2, apoE3 and apoE4. APOE ε4 is a major genetic risk factor for cardiovascular disease (CVD) and Alzheimer's disease (AD). ApoE mediates cholesterol metabolism by binding various receptors. The low-density lipoprotein receptor (LDLR) has a high affinity for apoE, and is the only member of its receptor family to demonstrate an apoE isoform specific binding affinity (E4>E3>>E2). Evidence suggests that a functional interaction between apoE and LDLR influences the risk of CVD and AD. We hypothesize that the differential cognitive effects of the apoE isoforms are a direct result of their varying interactions with LDLR. To test this hypothesis, we have employed transgenic mice that express human apoE2, apoE3, or apoE4, and either human LDLR (hLDLR) or no LDLR (LDLR-/-). Our results show that plasma and brain apoE levels, cortical cholesterol, and spatial memory are all regulated by isoform-dependent interactions between apoE and LDLR. Conversely, both anxiety-like behavior and cued associative memory are strongly influenced by APOE genotype, but these processes appear to occur via an LDLR-independent mechanism. Both the lack of LDLR and the interaction between E4 and the LDLR were associated with significant impairments in the retention of long term spatial memory. Finally, levels of hippocampal apoE correlate with long term spatial memory retention in mice with human LDLR. In summary, we demonstrate that the apoE-LDLR interaction affects regional brain apoE levels, brain cholesterol, and cognitive function in an apoE isoform-dependent manner.

Original languageEnglish
Pages (from-to)150-162
Number of pages13
JournalNeurobiology of Disease
StatePublished - Apr 2014

Bibliographical note

Funding Information:
The authors would like to thank Erin Bidiman, Massarra Eiwaz, Jackie Lanz, Tessa Marzulla, Blair Stewart, Dawn Cote and Dr. Damian Zuloaga for their invaluable assistance. This work was supported by National Institute of Environmental Health Sciences grant T32-ES07060 , National Heart, Lung, and Blood Institute T32-HL094294 , and the development account of JR. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. LAJ was also supported by the Collins Medical Trust and the Oregon Tax Check-off Program for Alzheimer's Research administered by the Layton Aging & Alzheimer's Disease Center, Oregon Health & Science University .


  • Alzheimer's
  • ApoE
  • Apolipoprotein E
  • Cholesterol
  • Hippocampus
  • LDLR
  • Low density lipoprotein receptor
  • Memory

ASJC Scopus subject areas

  • Neurology


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